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Translational Science

Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma

Jessica M. Rusert, Edwin F. Juarez, Sebastian Brabetz, James Jensen, Alexandra Garancher, Lianne Q. Chau, Silvia K. Tacheva-Grigorova, Sameerah Wahab, Yoko T. Udaka, Darren Finlay, Huriye Seker-Cin, Brendan Reardon, Susanne Gröbner, Jonathan Serrano, Jonas Ecker, Lin Qi, Mari Kogiso, Yuchen Du, Patricia A. Baxter, Jacob J. Henderson, Michael E. Berens, Kristiina Vuori, Till Milde, Yoon-Jae Cho, Xiao-Nan Li, James M. Olson, Iris Reyes, Matija Snuderl, Terence C. Wong, David P. Dimmock, Shareef A. Nahas, Denise Malicki, John R. Crawford, Michael L. Levy, Eliezer M. Van Allen, Stefan M. Pfister, Pablo Tamayo, Marcel Kool, Jill P. Mesirov and Robert J. Wechsler-Reya
Jessica M. Rusert
1Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Edwin F. Juarez
2Department of Medicine, University of California San Diego, La Jolla, California.
3Moores Cancer Center, University of California San Diego, La Jolla, California.
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  • ORCID record for Edwin F. Juarez
Sebastian Brabetz
4Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
5Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
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James Jensen
2Department of Medicine, University of California San Diego, La Jolla, California.
3Moores Cancer Center, University of California San Diego, La Jolla, California.
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Alexandra Garancher
1Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Lianne Q. Chau
1Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Silvia K. Tacheva-Grigorova
1Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Sameerah Wahab
1Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Yoko T. Udaka
6Rady Children's Hospital San Diego, San Diego, California.
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Darren Finlay
7Tumor Microenvironment and Cancer Immunology Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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  • ORCID record for Darren Finlay
Huriye Seker-Cin
4Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
5Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
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Brendan Reardon
8Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
9Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Susanne Gröbner
4Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
5Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
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Jonathan Serrano
10Department of Pathology, NYU Langone Health, New York, New York.
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Jonas Ecker
4Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
11CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
12Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany.
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Lin Qi
13Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
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Mari Kogiso
13Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
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Yuchen Du
13Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
14Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University, Chicago, Illinois.
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Patricia A. Baxter
13Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
14Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University, Chicago, Illinois.
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Jacob J. Henderson
15Papé Family Pediatric Research Institute, Department of Pediatrics, and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Michael E. Berens
16Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona.
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  • ORCID record for Michael E. Berens
Kristiina Vuori
7Tumor Microenvironment and Cancer Immunology Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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Till Milde
4Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
11CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
12Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany.
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Yoon-Jae Cho
15Papé Family Pediatric Research Institute, Department of Pediatrics, and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Xiao-Nan Li
13Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
14Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Northwestern University, Chicago, Illinois.
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James M. Olson
17Fred Hutchinson Cancer Research Center and Seattle Children's Hospital, Seattle, Washington.
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Iris Reyes
18Rady Children's Institute for Genomic Medicine, San Diego, California.
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Matija Snuderl
10Department of Pathology, NYU Langone Health, New York, New York.
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Terence C. Wong
18Rady Children's Institute for Genomic Medicine, San Diego, California.
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David P. Dimmock
18Rady Children's Institute for Genomic Medicine, San Diego, California.
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Shareef A. Nahas
18Rady Children's Institute for Genomic Medicine, San Diego, California.
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Denise Malicki
19Rady Children's Hospital, San Diego, California.
20Department of Pathology, University of California San Diego, La Jolla, California.
21Department of Pediatrics, University of California San Diego, La Jolla, California.
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John R. Crawford
19Rady Children's Hospital, San Diego, California.
21Department of Pediatrics, University of California San Diego, La Jolla, California.
22Department of Neurosciences, University of California San Diego, La Jolla, California.
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Michael L. Levy
19Rady Children's Hospital, San Diego, California.
23Department of Surgery, University of California San Diego, La Jolla, California.
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Eliezer M. Van Allen
8Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
9Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Stefan M. Pfister
4Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
5Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
12Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany.
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Pablo Tamayo
2Department of Medicine, University of California San Diego, La Jolla, California.
3Moores Cancer Center, University of California San Diego, La Jolla, California.
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Marcel Kool
4Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
5Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
24Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
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Jill P. Mesirov
2Department of Medicine, University of California San Diego, La Jolla, California.
3Moores Cancer Center, University of California San Diego, La Jolla, California.
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Robert J. Wechsler-Reya
1Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
18Rady Children's Institute for Genomic Medicine, San Diego, California.
21Department of Pediatrics, University of California San Diego, La Jolla, California.
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  • For correspondence: rwreya@sbpdiscovery.org
DOI: 10.1158/0008-5472.CAN-20-1655 Published December 2020
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Abstract

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor.

Significance: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Cancer Res 2020;80:5393–407

  • Received May 22, 2020.
  • Revision received September 4, 2020.
  • Accepted October 7, 2020.
  • Published first October 12, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Research: 80 (23)
December 2020
Volume 80, Issue 23
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Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma
Jessica M. Rusert, Edwin F. Juarez, Sebastian Brabetz, James Jensen, Alexandra Garancher, Lianne Q. Chau, Silvia K. Tacheva-Grigorova, Sameerah Wahab, Yoko T. Udaka, Darren Finlay, Huriye Seker-Cin, Brendan Reardon, Susanne Gröbner, Jonathan Serrano, Jonas Ecker, Lin Qi, Mari Kogiso, Yuchen Du, Patricia A. Baxter, Jacob J. Henderson, Michael E. Berens, Kristiina Vuori, Till Milde, Yoon-Jae Cho, Xiao-Nan Li, James M. Olson, Iris Reyes, Matija Snuderl, Terence C. Wong, David P. Dimmock, Shareef A. Nahas, Denise Malicki, John R. Crawford, Michael L. Levy, Eliezer M. Van Allen, Stefan M. Pfister, Pablo Tamayo, Marcel Kool, Jill P. Mesirov and Robert J. Wechsler-Reya
Cancer Res December 1 2020 (80) (23) 5393-5407; DOI: 10.1158/0008-5472.CAN-20-1655

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Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma
Jessica M. Rusert, Edwin F. Juarez, Sebastian Brabetz, James Jensen, Alexandra Garancher, Lianne Q. Chau, Silvia K. Tacheva-Grigorova, Sameerah Wahab, Yoko T. Udaka, Darren Finlay, Huriye Seker-Cin, Brendan Reardon, Susanne Gröbner, Jonathan Serrano, Jonas Ecker, Lin Qi, Mari Kogiso, Yuchen Du, Patricia A. Baxter, Jacob J. Henderson, Michael E. Berens, Kristiina Vuori, Till Milde, Yoon-Jae Cho, Xiao-Nan Li, James M. Olson, Iris Reyes, Matija Snuderl, Terence C. Wong, David P. Dimmock, Shareef A. Nahas, Denise Malicki, John R. Crawford, Michael L. Levy, Eliezer M. Van Allen, Stefan M. Pfister, Pablo Tamayo, Marcel Kool, Jill P. Mesirov and Robert J. Wechsler-Reya
Cancer Res December 1 2020 (80) (23) 5393-5407; DOI: 10.1158/0008-5472.CAN-20-1655
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